Investigations to date suggest that 1) oxygen metabolite mediated myocardial ischemia reperfusion injury exists; 2) it causes myocardial dysfunction and arrhythmias; and 3) the perfused-ischemic borderzone is the site of metabolic and functional electrophysiologic instability. Our hypothesis is that: Recover of Cardiac Function in Hearts Subjected to an Ischemia/Reperfusion Insult can be Enhanced by Prior Induction of Myocardial Tolerance to Oxidant Stress. To address this hypothesis, we will employ a standard isolated heart model of global ischemia which affords the advantages of a controlled ischemic insult free from confounding variables of blood born mediators. We have found that sublethal doses of endotoxin (ETX) or its more distal cytokine mediators tumor necrosis factor (TNF) and interleukin-1 (IL-1) given to rats 36 hours prior to isolated heart preparation induce protection from ischemia reperfusion injury. This protection relates to increased endogenous myocardial oxidant defense mechanisms at 36 hours and early (6 hours) neutrophil mediated myocardial oxidant stress. Our specific aims will investigate: 1) pathophysiology (heart function, hydrogen peroxide levels, and antioxidant enzymes); 2) histopathology (heart neutrophil accumulation); and 3) the mechanism (via xanthine oxidase depletion, neutrophil depletion, and oxygen metabolite scavenger treatment) of ETX, TNF, and IL-1 induced protection. We acknowledge that these are highly focused goals, but believe that progress in this area will have direct application to the million or more Americans each year with ischemia related cardiac dysfunction and dysrhythmias.